In general, the invention relates to methods and compositions for the treatment and diagnosis of endothelial disorders and angiogenic disorders.
Angiogenesis is the formation of new blood vessels from pre-existing vessels. This multi-step process involves signaling to endothelial cells, which results in (1) dissolution of the membrane of the originating vessel, (2) migration and proliferation of the endothelial cells, and (3) formation of a new vascular tube by the migrating cells. While this process is employed by the body in beneficial physiological events such as wound healing, the cyclic build-up of the endometrial lining after menses, and myocardial infarction repair, it is also involved in pathological conditions such as cancer and cancer metastasis; atherosclerosis; inflammatory conditions, such as chronic inflammation and rheumatoid arthritis; pathologic dermatological processes, such as dermatitis, psoriasis, hemangiomas, and Kaposi's sarcoma; as well as eye diseases such as ocular neovascular diseases, diabetic retinopathy, and macular degeneration.
In addition to their role in angiogenesis, endothelial cells are also involved in maintaining vascular health. Endothelial cells form flat, pavement-like patterns on the inside of the vessels and at the junctions between cells there are overlapping regions of endothelial cells, which help to seal the vessel. Endothelial cells are selective filters which regulate the passage of gases, fluid and various molecules across their cell membranes. Different organs have different types of endothelium: some leaky and some very tightly bound.
Endothelial cell health is critical to the maintenance of vascular health and vascular diseases are often caused by injury to the endothelial cells. Once the endothelium is injured, large molecules (e.g., macrophages, lipid, and cholesterol) are allowed to escape through the endothelium and form deposits in the smooth muscle cells in the arterial wall. Macrophages also pass through and accumulate fat (lipid and cholesterol) deposits. The most common form of endothelial cell disease is arteriosclerosis, where the deposition of cholesterol in the sub-endothelial layer of arteries contributes to the pathogenesis of the disease. This process is very slow, but there is a gradual accumulation of this fatty and fibrous material which not only makes the normally elastic artery sclerotic but the deposits, known as “plaques” may lead to a narrowing of the artery and facilitate the formation of a blood clot or a thrombosis. Myocardial infarction and stroke are additional consequences that result from endothelial cell injury or a disruption to the endothelial layers of the arteries.
Endothelial cells are also involved in regulation of inflammatory pathways via regulation of cytokines and the cytokine pathways. For example, during rheumatoid arthritis, endothelial cells become activated and express adhesion molecules and chemokines, leading to leukocyte migration from the blood into the tissue. Endothelial cell permeability increases, leading to edema formation and swelling of the joints.
Maintenance of endothelial cell health and the angiogenic balance is critical to the prevention of diseases and disorders that are caused by or related to endothelial disorders or inappropriate angiogenesis. Therefore, methods that maintain and promote endothelial cell health and that maintain the angiogenic balance within an organism are needed for the treatment and prevention of a variety of pathogenic processes associated with inappropriate angiogenesis and endothelial cell injury or dysfunction.